Based on a recent discovery in rodents, for the first time, osteocalcin (OC), a major bone formation protein uniquely secreted by osteoblasts, may play a crucial role in endocrine regulation of energy metabolism by enhancing b-cell proliferation, insulin production, insulin sensitivity and adiponectin expression as a feedback loop of Leptin's regulation of osteoblasts. This new evidence suggests that bone cells not only function locally on the skeleton, but may also be involved in the pathogenesis of insulin resistance and the metabolic syndrome. However, the underlying mechanisms for how OC interacting with adipocytes, pancreatic 2 cells and other molecules functionally involved in glucose homeostasis are still unclear. The existence of biological evidence linking "endo-phenotypes" of often quite distinct diseases raises another possibility that diseases may not be as independent of each other as is often assumed. Our study attempts to link two systems: bone and energy metabolisms. Thus the underlying hypothesis of this proposal is that there are shared genetic variants that regulate both serum OC and metabolic risk factors (metabolic syndrome risk factor clustering: a combination of risk factors including central obesity, hyperglycemia, dyslipidemia, and hypertension). In this application we are proposing a genome-wide association (GWA) approach in the Framingham Heart Study to identify (1) novel genetic variants for serum OC and (2) shared genetic determinants with directly pleiotropic effects on both serum OC and metabolic risk factors (including waist circumference, systolic blood pressure, fasting triglycerides, fasting HDL cholesterol, fasting plasma glucose, fasting plasma insulin, adiponectin concentrations and insulin resistance indices such as HOMA-IR and QUICKI). The state-of-the-art GWA analytical approaches will be used including the multipe-phenotyping GWA analysis using a recent developed Principle of Heritability method, weighted hypotheses based on prior information, and a newly developed structure modeling to infer the directly pleotropic effects. Bioinformatics approaches, such as pathway network analyses, gene- set enrichment test, and eSNP analyses will also be applied. We will use already collected phenotype data and available high-density 550K Affymetrix genotyping data. The proposed work will take advantage of the rich available data and large sample size of the Framingham Heart Study. This will be the first human study using GWA approach to attempt to translate the OC findings from animals, which will afford the opportunity to generate new hypotheses to understand the signaling pathways and underlying biological mechanisms behind the crosstalk, as it is not fully understood how this bone protein regulates glucose metabolism, insulin secretion and insulin sensitivity. Confirmation of these findings in humans could also have important implications for women who commonly suffer from the morbid and sometimes mortal complications of both osteoporosis and cardiovascular disease risk factor clustering, metabolic syndrome. PUBLIC HEALTH RELEVANCE: Recent animal studies have showed that osteocalcin, an important bone protein, involves in the endocrine regulation of energy metabolism. However, the underlying mechanisms for how osteocalcin interacting with adipocytes and pancreatic 2 cells are still unclear. Our study will be the first human study using state-of-the-art genome-wide association approaches to attempt to identify novel genetic variants shared by both osteocalcin and metabolic risk factors, which will provide valuable insight into potential molecular targets that will help further understanding the underlying mechanisms of communication between skeleton and energy metabolism.